Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling

The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination. Tight somatic regulation of this signal is essential, as uncontrolled nuclear accumulation of beta-catenin can cause developmental defects and tumorigenesis in the adult organism. The adenomatous polyposis coli gene (APC) is a major controller of the Wnt pathway and is essential to prevent tumorigenesis in a variety of tissues and organs. Here, we have investigated the effect of different mutations in Apc on the differentiation potential of mouse embryonic stem (ES) cells. We provide genetic and molecular evidence that the ability and sensitivity of ES cells to differentiate into the three germ layers is inhibited by increased doses of beta-catenin by specific Apc mutations. These range from a severe differentiation blockade in Apc alleles completely deficient in beta-catenin regulation to more specific neuroectodermal, dorsal mesodermal and endodermal defects in more hypomorphic alleles. Accordingly, a targeted oncogenic mutation in Catnb also affects the differentiation potential of ES cells. Expression profiling of wildtype and Apc-mutated teratomas supports the differentiation defects at the molecular level and pinpoints a large number of downstream structural and regulating genes. Chimeric experiments showed that this effect is cell-autonomous. Our results imply that constitutive activation of the Apc/beta-catenin signaling pathway results in differentiation defects in tissue homeostasis, and possibly underlies tumorigenesis in the colon and other self-renewing tissues.     

RandomX-chromosome inactivation in interspecific hybrids ofMeriones libycus (♂) ×Meriones shawi (♀) (Rodentia: Gerbillinae)

Résumé Des cultures obtenues à partir d'hybrides femelles entre deux espèces deMeriones à 44 chromosomes et différant par l'acrocentrie (M. shawi) ou la métacentrie (M. libycus) de l'X ont permis l'étude de clones cellulaires. C'est alors tantôt l'X métacentrique, tantôt l'X acrocentrique qui se révèle inactivé («latereplicating»). Bien que la proportion 1/1, significative d'une inactivation due uniquement au hasard, n'ait pas été rigoureusement observée, ces résultats sont nettement en faveur de l'hypothèse deLyon.

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Supported by Project No. 417 from the U.S. Children's Bureau and National Science Foundation (Grant No. GB 5676X).     

Elevated histidine decarboxylase activity in the kidney of the pregnant mouse

Zusammenfassung Die Fähigkeit,¹⁴C-Histamin aus¹⁴C-Histidin zu bilden, steigt in der Niere der schwangeren Maus enorm an. Dieses Organ ist deshalb eine der reichsten Quellen von tierischer Histidindecarboxylase.     

Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype

The immune system must distinguish not only between self and non-self, but also between innocuous and pathological foreign antigens to prevent unnecessary or self-destructive immune responses. Unresponsiveness to harmless antigens is established through central and peripheral processes. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10) and suppression of T-helper cells; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype. Our findings identify an endogenous receptor-mediated event that drives Tr1 differentiation and suggest that the complement system has a previously unappreciated role in T-cell-mediated immunity and tolerance.     

A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response

Fifty million new infections with Mycobacterium tuberculosis occur annually, claiming 2-3 million lives from tuberculosis worldwide. Despite the apparent lack of significant genetic heterogeneity between strains of M. tuberculosis, there is mounting evidence that considerable heterogeneity exists in molecules important in disease pathogenesis. These differences may manifest in the ability of some isolates to modify the host cellular immune response, thereby contributing to the observed diversity of clinical outcomes. Here we describe the identification and functional relevance of a highly biologically active lipid species-a polyketide synthase-derived phenolic glycolipid (PGL) produced by a subset of M. tuberculosis isolates belonging to the W-Beijing family that show 'hyperlethality' in murine disease models. Disruption of PGL synthesis results in loss of this hypervirulent phenotype without significantly affecting bacterial load during disease. Loss of PGL was found to correlate with an increase in the release of the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukins 6 and 12 in vitro. Furthermore, the overproduction of PGL by M. tuberculosis or the addition of purified PGL to monocyte-derived macrophages was found to inhibit the release of these pro-inflammatory mediators in a dose-dependent manner.     

Acclimation of ecosystem CO2 exchange in the Alaskan Arctic in response to decadal climate warming

Long-term sequestration of carbon in Alaskan Arctic tundra ecosystems was reversed by warming and drying of the climate in the early 1980s, resulting in substantial losses of terrestrial carbon. But recent measurements suggest that continued warming and drying has resulted in diminished CO2 efflux, and in some cases, summer CO2 sink activity. Here we compile summer CO2 flux data for two Arctic ecosystems from 1960 to the end of 1998. The results show that a return to summer sink activity has come during the warmest and driest period observed over the past four decades, and indicates a previously undemonstrated capacity for ecosystems to metabolically adjust to long-term (decadal or longer) changes in climate. The mechanisms involved are likely to include changes in nutrient cycling, physiological acclimation, and population and community reorganization. Nevertheless, despite the observed acclimation, the Arctic ecosystems studied are still annual net sources of CO2 to the atmosphere of at least 40 g C m(-2) yr(-1), due to winter release of CO2, implying that further climate change may still exacerbate CO2 emissions from Arctic ecosystems.     

Oxygen content of transmembrane proteins over macroevolutionary time scales

We observe that the time of appearance of cellular compartmentalization correlates with atmospheric oxygen concentration. To explore this correlation, we predict and characterize the topology of all transmembrane proteins in 19 taxa and correlate differences in topology with historical atmospheric oxygen concentrations. Here we show that transmembrane proteins, individually and as a group, were probably selectively excluding oxygen in ancient ancestral taxa, and that this constraint decreased over time when atmospheric oxygen levels rose. As this constraint decreased, the size and number of communication-related transmembrane proteins increased. We suggest the hypothesis that atmospheric oxygen concentrations affected the timing of the evolution of cellular compartmentalization by constraining the size of domains necessary for communication across membranes.